AJNR Am J Neuroradiol 19:523528, March 1998

Imaging Patterns of Neonatal Hypoglycemia

A. James Barkovich, Firas Al Ali, Howard A. Rowley, and Nancy Bass

PURPOSE: Our purpose was to report the patterns of injury observed in five patients who
suffered brain damage consequent to neonatal hypoglycemia.
METHODS: The imaging studies and clinical records of five patients with brain damage
caused by neonatal hypoglycemia were reviewed retrospectively. Patterns of injury were compared with those described in the literature and those seen in neonatal hypoxic-ischemic injury.
RESULTS: Diffuse cortical and subcortical white matter damage was seen, with the parietal
and occipital lobes affected most severely. Globus pallidus injury was present in one patient
who had the most severe cortical injury.
CONCLUSION: We found a specific pattern of injury that correlates well with the sparse
pathologic and imaging reports on neonatal hypoglycemia. We speculate that the patterns of
damage are the result of regional hypoperfusion and excitatory toxicity with cell-type-specific
injury.
Although hypoglycemia may be common among
neonates (1), brain damage resulting from isolated
neonatal hypoglycemia is rare. As a result, few cases
have been reported in the pediatric, neurologic, or
radiologic literature (1 6). We have recently had the
opportunity to review the imaging studies of five infants who suffered brain damage as a result of neonatal hypoglycemia. All had similar patterns of
damage to the brain. We report the imaging characteristics of these patients, compare the findings with
those few cases reported previously, and attempt to
relate the patterns to the underlying physiology.

of 3 days and 26 days. Follow-up imaging studies (a total of two

CT scans and two MR examinations) were obtained in three
patients 10 days to 2 months after the original studies. All CT
and MR studies were obtained without the use of intravenous
contrast material.

Results
Clinical Data
All patients were neonates who were born after
uneventful pregnancies and deliveries. The two undernourished neonates were classified as small for
gestational age (less than 10th percentile) and the one
with hyperinsulinemia was large for gestational age;
the other two were considered normal in size. All had
normal immediate postnatal courses, with 5-minute
Apgar scores of 8 or 9. All initially presented as a
result of seizure activity. In the two patients who were
small for gestational age, seizures developed in the
first day (one at 14 hours, one at 19 hours). One
patient was still in the hospital when seizures developed; in the second, seizures developed at home and
the infant was not brought back to the hospital for
care until the age of 40 hours, when his increasing
irritability began to concern his parents. In both cases,
initial glucose levels, obtained with Chem strips, were
zero. Serum glucose levels were obtained immediately, with values of less than 3 mg/dL for both patients. The patients were treated immediately with a
bolus of 10% glucose followed by rapid drip infusion,
but the hypoglycemia was difficult to treat and required continuous infusion for 36 hours in one patient
and 48 hours in the other before glucose levels stabilized. Laboratory studies for underlying hormonal abnormalities and inborn errors of metabolism were
negative.

Methods
The clinical records and imaging studies of five patients were
reviewed retrospectively. Two were ultimately determined to
have neonatal hyperinsulinemia, two were thought to have
diminished glycogen and lipid stores as well as impaired gluconeogenesis subsequent to intrauterine malnutrition, and the
fifth patient was ultimately determined to have a transient
metabolic disorder.
Two patients had axial computed tomography (CT) studies
(5-mm-thick sections) and all five had magnetic resonance
(MR) imaging studies. MR examinations included sagittal 3- to
5-mm-thick T1-weighted sequences and axial 4- to 5-mm-thick
spin-echo T2-weighted sequences in all patients, and coronal
and axial 3- to 5-mm-thick T1-weighted sequences in three
patients. Initial examinations were performed between the ages
Received May 8, 1997; accepted after revision September 15.
From the Departments of Radiology (Section of Neuroradiology)
(A.J.B., F.A.A., H.A.R.), Neurology (A.J.B., H.A.R., N.B.), and Pediatrics (A.J.B., N.B.), University of California, San Francisco.
Address reprint requests to A. James Barkovich, MD, Department of Radiology, Section of Neuroradiology, Rm L371, University of California, San Francisco, 505 Parnassus Ave, San Francisco,
CA 94143.

American Society of Neuroradiology

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AJNR: 19, March 1998

FIG 1. Patient 1: AC are from MR

imaging study at age 13 days, D is
from study at age 27 days.
A, Parasagittal spin-echo (550/11/2)
image shows abnormal hyperintensity
(arrows) of the parietal and occipital
cerebral cortex.
B, Axial spin-echo (3000/120/1) image shows abnormal hyperintensity
(open arrows) in the globi palladi and
mixed hypointensity and hyperintensity (solid arrows) in the occipital cortex and white matter.
C, Coronal spin-echo (550/11/2) image shows hyperintensity of the globi
palladi (open arrows). The cortex at the
depths of the cortical sulci (solid arrows) is hyperintense as well.
D, Parasagittal spin-echo (550/11/2)
image at age 27 days shows marked
tissue loss, most prominently in the parietal and occipital lobes (arrows).

In the other three patients, who were not small for

gestational age, poor feeding was reported to develop
at age 2 to 3 days. Two were noted to have periods of
apnea. One was discovered to have a large secundum
atrial septal defect. Seizures, manifested as focal jerking of the arms or legs, developed between 40 hours
and 80 hours after birth. Two of the patients were not
brought to the hospital until the seizures started,
whereas the third was already in the hospital undergoing a workup related to poor feeding and apnea.
All three children in this group were somewhat slow
to respond to intravenous glucose therapy; in two, the
serum glucose levels did not stabilize, even after 2
days of glucose infusion. In both these infants, insulin
levels were obtained and showed marked elevation.
Ultimately, the diagnosis of congenital hyperinsulinism of the newborn, previously known as nesidioblastosis, was made in these patients, and near total pancreatectomies were performed. In the third patient,
multiple abnormalities were present on the urine organic and amino acid screens; therefore, this infant
was classified as having a generalized organic acidemia by the physicians on the child neurology and
metabolic disease services. As the infant has matured,
his ability to generate and metabolize glucose has
normalized; he is normoglycemic without therapy at
the present time.
None of the patients had episodes of hypotension
or hypoxia during their neonatal course.

Neuroimaging
The neuroimaging studies of all patients showed
significant brain damage, with disproportionate involvement of the parietal and occipital lobes of the
cerebral hemispheres. In one of the patients who was
small for gestational age, the brain damage was more
extensive, extending into the posterior portions of the
frontal lobes and involving the globus pallidus (Fig 1).
In the other four patients, the damage was restricted
to the parietal and occipital lobes, involving both the
cortex and underlying white matter (Fig 2). In two
patients, CT scans were obtained in the first 5 days of
life. They revealed edema in the parietal and occipital
cortices (Fig 2), with normal-appearing basal ganglia.
Ages at the time of the initial MR study ranged from
13 to 27 days. These studies showed T1 and T2 prolongation in the parietal and occipital white matter,
with mixed signal intensity in the cerebral cortex (Figs
1 and 2). Some areas, particularly the deeper cortex,
showed T1 and T2 shortening, whereas most of the
affected cortex showed T2 prolongation (Fig 2). In
the patient with the most extensive cerebral damage,
T1 shortening and T2 prolongation were seen in the
globus pallidus bilaterally (Fig 1). Short-term follow-up studies showed developing atrophy with cystic
encephalomalacia in affected regions of the brain
(Fig 1). The only available long-term follow-up study,

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NEONATAL HYPOGLYCEMIA

525

FIG 2. Patient 2.
A, Axial noncontrast CT scan on
postnatal day 2 shows diffuse cortical
edema, most severe in the parietal and
occipital lobes (arrows).
B, Sagittal spin-echo (550/11/2) MR
image on postnatal day 19 shows low
attenuation (arrows) of the parietal and
occipital cortex and white matter.
C, Axial spin-echo (3000/120/1) image on postnatal day 19 shows abnormal hyperintensity (arrows), primarily in
the parietal and occipital lobes.
D, Axial noncontrast CT scan at age
2 months shows large areas of encephalomalacia (arrows) in the parietooccipital regions bilaterally.

at age 3 months, showed large areas of cystic degeneration in the parietal and occipital lobes (Fig 2).

Discussion
The reported rate of occurrence of neonatal hypoglycemia varies considerably, depending on the definition of hypoglycemia and the population of infants
studied (7). Neonatal hypoglycemia is probably underrecognized, because common symptoms, such as
stupor, jitteriness, and seizures, may be lacking or
inconspicuous in many affected neonates (1). The
definition of hypoglycemia in infants varies with the
maturational state of the brain: less mature infants
can withstand lower glucose levels than more mature
ones, and mature infants can withstand lower levels
than adults. The most widely accepted definition of
significant hypoglycemia in the newborn is a wholeblood glucose concentration of less than 30 mg/dL in
term infants (a level of 30 mg/dL causes confusion
and seizures in an adult [8], in whom normal levels
are greater than 45 to 50 mg/dL) and less than 20
mg/dL in preterm infants (9). On the basis of these
criteria, up to 8% of low-risk infants may suffer an
episode of hypoglycemia, typically at 3 to 4 hours
after delivery (7).

Cornblath and Schwartz (9) classified neonatal hypoglycemia into four clinical categories, which were
adapted by Volpe (1) on the basis of prenatal maternal or fetal condition and the presence, severity, and
time of onset of symptoms. Category one, transitional-adaptive hypoglycemia, is characterized by a very
early postnatal onset of mild, brief hypoglycemia that
responds rapidly to glucose administration. These infants often have diabetic mothers or erythroblastosis,
and have difficulty adapting to the metabolic changes
accompanying transition to extrauterine life. Category two, secondary-associated hypoglycemia, is characterized by onset of relatively mild hypoglycemia of
short duration early in the first postnatal day, with
rapid response to glucose. In general, these infants
have been subjected to an associated disorder of the
CNS, such as hypoxic-ischemic injury, intracranial
hemorrhage, or bacterial sepsis. Category three, classic-transient hypoglycemia, tends to present toward
the end of the first day with moderate to severe
hypoglycemia that can be of prolonged duration and
that requires large amounts of glucose before a response is noted. These infants are almost always small
for gestational age, owing to intrauterine undernutrition, with resultant diminished glycogen and lipid

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stores as well as impaired gluconeogenesis. Patients

in category four, severe recurrent hypoglycemia, are
usually born at term and present with severe, prolonged hypoglycemia. The time of onset of the hypoglycemia is variable, and the hypoglycemia may persist in spite of early glucose therapy. Most infants in
this group have primary disorders of glucose homeostasis. Causes include Beckwith-Wiedemann syndrome, congenital hyperinsulinism of the newborn
(nesidioblastosis), b-cell hyperplasia, endocrine deficiencies, and inborn errors of metabolism. Two of our
patients seem to belong in category three and three in
category four. Of importance is the fact that despite
several different causes of hypoglycemia in our patients, the pattern of damage, with involvement of
primarily the parietal and occipital lobes, was nearly
identical. Therefore, the pattern of damage detected
by neuroimaging seems to principally reflect injury
from hypoglycemia and not that of an underlying
disorder.
The causes underlying the ability of the less mature
brain to withstand lower levels of glucose have not
been completely established. In the mature (adult)
brain, the levels of phosphocreatine and adenosine
triphosphate (ATP) decrease very rapidly after the
onset of severe hypoglycemia (10, 11). As a result,
proteins and phospholipids are broken down to form
endogenous amino acids and free fatty acids, respectively. These may then be channeled into oxidative
pathways as alternative substrates for energy production. When proteins and free fatty acids are used as
energy sources, ammonia and arachidonic acid (which
generates free radicals) are produced, leading to cellular injury (10, 12, 13). With continued hypoglycemia, membrane homeostasis is lost, the electroencephalogram becomes isoelectric, and irreversible
injury ensues.
In the immature (neonatal) brain, phosphocreatine
and ATP levels in neurons are maintained despite low
glucose levels (14). In fact, the cerebral metabolic
rate for oxygen is unchanged in hypoglycemic neonates (15). Newborns are able to maintain consciousness at much lower glucose levels than are mature
subjects (1). Probable reasons for the maintenance of
energy profiles and neurologic function include the
ability of the newborn brain cells to utilize lactate as
an energy source (15, 16) and the low energy requirements of the immature neurons resulting from the
low level of neuronal activity (1). A third factor contributing to the resistance of the newborn brain to
hypoglycemia is the relatively minor effect of hypoglycemia upon cardiovascular function of the newborn (14). The immature heart has substantial stores
of energy-rich carbohydrates that can be converted to
glucose and, moreover, can use fuels other than glucose for energy (1, 17, 18); thus, cerebral perfusion
and oxygenation is maintained during neonatal hypoglycemia.
The ability to utilize alternative energy sources and
the maintenance of cardiac output and cerebral perfusion are likely to be the most important differences
in the patterns of brain injury seen in neonatal hypo-

AJNR: 19, March 1998

glycemia versus neonatal hypoxia (6, 19 23). When

hypoxia occurs in the newborn, cardiac function is
disturbed and cardiac output diminished. The diminished cardiac output, in conjunction with the impaired cerebrovascular autoregulation that accompanies hypoxia (24, 25), leads to ischemia and resultant
lack of oxygen and glucose delivery to the brain. Thus,
ischemic and hypoglycemic injury are superimposed.
As hypoglycemia seems to potentiate the effects of
hypoxia (1), the effects on the brain are devastating.
This observation explains the identical pathologic
patterns in infants with hypoxia and in those with
combined hypoxia and hypoglycemia, as reported in
the literature (26). In both groups of patients, in fact,
the same sets of neurons suffer the same condition of
combined hypoxia and hypoglycemia.
Hypoglycemia in adults leads to two patterns of
damage: regional and cell-type specific. Insulin-induced coma in rats results in regional loss of autoregulation in the cortex, thalamus, hippocampus, and
medial geniculate bodies, with preservation of the
cerebellum, brain stem, and hypothalamus (27).
Moreover, delayed hypoperfusion (25% to 40% of
control cerebral blood flow) has been documented in
the forebrain and hippocampus (28). Hypoglycemia
disrupts protein synthesis in the superficial layers of
the cortex, in the caudate, in the putamen, and in
certain cell populations of the hippocampus (CA1
and CA3 pyramidal cells, dentate crest granule cells)
(10), whereas cerebellar and brain stem protein synthesis is relatively unaffected. Rates of protein synthesis may simply reflect the available energy within
the cell, with relative preservation in the cerebellum
and brain stem due to a greater activity of glucose
transport mechanisms in those areas (29). The contribution of selective changes in regional autoregulation and protein synthesis disruption have not been
studied in neonatal groups.
Our findings of diffuse brain damage, with the most
severe injury localized primarily to the parietal and
occipital cortex of the brain, verify the observations of
Banker (5), Anderson et al (3, 4), and Spar et al (2)
concerning the diffuse nature of hypoglycemic brain
injury in the newborn and the posterior cortical localization of the most severely injured regions. The
reason that the parietal and occipital lobes are most
severely affected is not obvious. The pattern of damage does not match the pattern of normal glucose
uptake in neonates, as determined by positron emission tomography (30), indicating that it is not a simple
matter of demand and supply of glucose as an energy
source. One possible reason for the pattern of damage may relate to the development of receptors for
excitatory amino acids (EAAs). The literature is replete with evidence that excessive release of excitatory amino acids (excitotoxins), such as glutamate and
aspartate, into the synaptic cleft results in the selective death of the postsynaptic neurons (selective neuronal necrosis) in conditions such as hypoxia-ischemia, seizures, and trauma (3134). Excitotoxins,
particularly aspartate, also appear to be involved in
neuronal injury resulting from hypoglycemia (3538).

AJNR: 19, March 1998

Moreover, experimental evidence indicates that the

location of neurons with cell surface receptors for
excitatory amino acids, such as N-methyl D-aspartate
(NMDA), changes as development proceeds (39, 40).
As cell injury does not occur in the absence of EAA
receptors, the ontogenic changes in the receptor locations may explain the different location and pattern
of damage in infants as compared with older children
and adults (the corpus striatum and hippocampi [10,
41, 42]). Although the parietal and occipital cortices
are not known sites of NMDA receptors in the neonatal period, the neonatal globus pallidus, which was
injured in one of our patients, has high concentrations
of receptors; the corpus striatum has high concentrations of NMDA receptors in adults (39, 40).
The ontogenic changes in NMDA receptor location
have also been suggested as a cause of the changing
patterns of brain injury resulting from profound
hypoxic-ischemic injury in infants, since the locations of
EAA receptors are similar to those damaged in hypoxia
and ischemia (21, 22). The pattern of damage in neonatal hypoxic-ischemic injury, however, is distinct from
that in neonatal hypoglycemia. This apparent discrepancy can be explained by taking into account the decreased cerebral perfusion that accompanies asphyxia.
As discussed earlier, cardiac output and, thus, global
cerebral perfusion are maintained in hypoglycemia.
Therefore, one possibility is that a difference in regional
blood flow may contribute to hypoglycemic damage
through either loss of autoregulation or delayed hypoperfusion, as discussed above. Alternatively, neuronal
injury in hypoglycemia may be restricted to those areas
with well-developed EAA receptors able to be excited
by elevated levels of aspartate. In contradistinction, hypoxia is almost invariably accompanied by decreased cardiac output and compromised autoregulation, resulting
in decreased cerebral perfusion (24, 25). Location of
brain injury in hypoxia, therefore, is determined by the
degree of cardiac impairment, metabolic requirements
of the cells (which are dependent on the state of regional metabolic activity), availability of collateral blood
flow, and developmental state of the EAA receptors,
particularly those for glutamate.
The question arises as to why the globi palladi were
injured in just one of our five patients. Based on the
fact that the patient with injury to the globus pallidus
was the one with the most extensive and severe cortical injury, we speculate that the neonatal globus
pallidus is less susceptible to hypoglycemic injury than
is the parietooccipital cortex, but more so than the
rest of the structures in the brain. If this is so, then
this patient presumably had hypoglycemia of greater
severity or greater duration than the other patients.
However, we have no good records of precisely how
long the hypoglycemia was present in any of these
patients, so this remains pure speculation. One might
also venture that there may have been a component
of hypoxia in this patient that was not present in the
others and that the combined hypoxic-hypoglycemic
injury was responsible for the globus pallidus injury.
However, no documented hypoxia was present in any
of our patients.

NEONATAL HYPOGLYCEMIA

527

The cause of the T1 and T2 shortening of the MR

signal arising from damaged cerebral cortex is most
likely the same as in hypoxic-ischemic injury. This
issue has been discussed in articles on hypoxic-ischemic injury (21, 22, 43), and does not need a lengthy
discussion here. Likely possibilities include calcification, petechial hemorrhage, and myelin degradation.
The exact cause of the signal changes awaits direct
pathologic-radiologic correlation.
The differential diagnosis of this pattern of damage
in the neonatal brain is not very extensive. Severe
sagittal sinus thrombosis can cause bilateral paramedian brain injury involving gray and white matter;
however, the thrombosed sinus can be identified by
MR imaging and, in addition, sinus thrombosis in
neonates is usually an incidental finding that does not
cause brain damage (44 46). Bilateral posterior cerebral artery compression resulting from cerebral
edema may cause bilateral occipital infarction (47),
but the pattern is different from that seen in the
patients reported here, as the calcarine regions are
specifically involved in arterial infarction but are
spared in neonatal hypoglycemia. Of importance,
neonatal hypoxic-ischemic injury (48, 49) does not
cause the pattern described here and, therefore, can
be clearly separated from neonatal hypoglycemia on
the basis of the imaging appearance of the injuries. It
is equally important to note that all the patients in
this study had an underlying problem that made them
susceptible to severe, prolonged hypoglycemia; there
is no evidence here or elsewhere indicating that neonates without underlying problems, such as growth
retardation or disorders of glucose homeostasis, can
sustain brain injury from hypoglycemia.

Conclusion
We have described the imaging findings in five
patients who suffered brain damage as a result of
neonatal hypoglycemia. CT and MR studies showed
damage primarily to the parietal and occipital lobes of
the cerebrum. Possible mechanisms of brain damage,
the reasons for the location of the damage, and potential reasons for the difference in location from that
in hypoxic-ischemic injury and adult hypoglycemic
injury have been discussed.

Acknowledgments
We thank Mark Ziegler, Sacramento, Calif, and William
Kelly, Palm Springs, Calif, for their help in accumulating information on two of these patients.

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